Genetic variation in CADM2 as a link between psychological traits and obesity

Morris, J. et al. (2019) Genetic variation in CADM2 as a link between psychological traits and obesity. Scientific Reports, 9, 7339. (doi: 10.1038/s41598-019-43861-9) (PMID:31089183) (PMCID:PMC6517397)

Abstract

CADM2 has been associated with a range of behavioural and metabolic traits, including physical activity, risk-taking, educational attainment, alcohol and cannabis use and obesity. Here, we set out to determine whether CADM2 contributes to mechanisms shared between mental and physical health disorders. We assessed genetic variants in the CADM2 locus for association with phenotypes in the UK Biobank, IMPROVE, PROCARDIS and SCARFSHEEP studies, before performing meta-analyses. A wide range of metabolic phenotypes were meta-analysed. Psychological phenotypes analysed in UK Biobank only were major depressive disorder, generalised anxiety disorder, bipolar disorder, neuroticism, mood instability and risk-taking behaviour. In UK Biobank, four, 88 and 172 genetic variants were significantly (p < 1 × 10−5) associated with neuroticism, mood instability and risk-taking respectively. In meta-analyses of 4 cohorts, we identified 362, 63 and 11 genetic variants significantly (p < 1 × 10−5) associated with BMI, SBP and CRP respectively. Genetic effects on BMI, CRP and risk-taking were all positively correlated, and were consistently inversely correlated with genetic effects on SBP, mood instability and neuroticism. Conditional analyses suggested an overlap in the signals for physical and psychological traits. Many significant variants had genotype-specific effects on CADM2 expression levels in adult brain and adipose tissues. CADM2 variants influence a wide range of both psychological and metabolic traits, suggesting common biological mechanisms across phenotypes via regulation of CADM2 expression levels in adipose tissue. Functional studies of CADM2 are required to fully understand mechanisms connecting mental and physical health conditions.

• Item Type: Articles
• Additional Information: The UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health, Scottish Government and Northwest Regional Development Agency. UK Biobank has also had funding from the Welsh Assembly Government and the British Heart Foundation. Data collection was funded by UK Biobank. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT- 2007-037273), AstraZeneca, the Swedish Research Council (8691), the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). IMPROVE was funded by the European Commission (LSHM-CT- 2007- 037273), the Swedish Heart-Lung Foundation, the Swedish Research Council (8691), the Knut and Alice Wallenberg Foundation, the Foundation for Strategic Research, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Programme of Karolinska Institutet and the Stockholm County Council and the Stockholm County Council (560183). S.E.H. is funded by the British Heart Foundation (PG008/08) and is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. SCARFSHEEP was supported by the Swedish Heart-Lung Foundation, the Swedish Research Council, the Strategic Cardiovascular Programme of Karolinska Institutet and the Stockholm County Council, the Strategic support for epidemiological research at Karolinska Institutet and the Stockholm County Council. JM was supported by a Lister Prize Summer Studentship. JW is supported by the JMAS Sim Fellowship for depression research from the Royal College of Physicians of Edinburgh (173558). AF is supported by an MRC Doctoral Training Programme Studentship at the University of Glasgow (MR/K501335/1). KJAJ is supported by an MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh. DJS acknowledges the support of the Brain and Behaviour Research Foundation (Independent Investigator Award 1930) and a Lister Prize Fellowship (173096). RJS is supported by a UKRI Innovation- HDR-UK Fellowship (MR/S003061/1). The funders had no involvement in the study design, analysis, interpretation or manuscript preparation.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morris, Dr. Rer. N Julia and Smith, Professor Daniel and Cullen, Dr Breda and Graham, Dr Nicholas and Lyall, Dr Laura and Bailey, Dr Mark and Ward, Dr Joey and Johnston, Ms Keira and Ferguson, Amy and Strawbridge, Dr Rona and Lyall, Dr Donald
• Authors: Morris, J., Bailey, M. E.S., Baldassarre, D., Cullen, B., de Faire, U., Ferguson, A., Gigante, B., Giral, P., Goel, A., Graham, N., Hamsten, A., Humphries, S. E., Johnston, K. J.A., Lyall, D. M., Lyall, L. M., Sennblad, B., Silveira, A., Smit, A. J., Tremoli, E., Veglia, F., Ward, J., Watkins, H., Smith, D. J., and Strawbridge, R. J.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > General Practice and Primary Care; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Scientific Reports 9: 7339
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
63234	1	MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16	George Baillie	Medical Research Council (MRC)	MR/K501335/1	MVLS GRADUATE SCHOOL
302131	0	Understanding the excess risk of cardiometabolic disease in individuals with serious mental illness	Jill Pell	Medical Research Council (MRC)	MR/S003061/1	HW - Public Health